Liver transplantation (LT) has evolved as the treatment of choice for patients with early stage hepatocellular carcinoma (HCC) and underlying cirrhosis of the liver. Acceptance of this treatment modality though, has been mostly based on small single center studies with very few patients followed beyond three years after transplantation. These reports have suggested that for properly selected patients with HCC, LT achieves 1 and 2 year survival rates similar to patients receiving LT for other, non-malignant diagnoses. However, several recent studies have pointed out that patients with HCC who wait for a prolonged time for LT have progression of their tumors beyond the favorable early stages. Consequently, many centers began applying loco-regional ablative treatments (AT) to HCC lesions to try and limit progression and/or improve post- LT outcomes. In addition, the Organ Procurement and Transplantation Network (OPTN) developed policy that allows patients with early stage HCC to receive priority on the waiting list greater than what would be assigned by the degree of underlying liver failure. With previous support from the NIDDK, we have assembled a large database of over 3000 cases containing detailed OPTN HCC listing, transplantation, pathology report, and post-LT follow-up data and have published some initial studies. Median follow-up for our complete cohort is 1085 days as of July 2008. Our data set is unique in that approximately half of the patients have not been treated with AT which provides an untreated control group, a significant omission in most studies published to date. In order to continue to justify the policy of increased priority for HCC, much more thorough, long-term analyses of LT results, must be accomplished and compared to other indications for liver transplantation than have been reported to date. This is the overall goal of this application. We have populated our database with longer follow-up data and clinically relevant covariates for at least 4 years after LT. Our large sample size will allow us to assess 4 year patient survival and survival benefit for LT in HCC patients compared with other indications and the degree to which selection bias may be affecting overall results, control for this selection bias with sophisticated statistical techniques, and perform robust subgroup analyses. We will also perform a long-term assessment of the efficacy of ATs and compare specific types of AT for improving 4 year post LT patient survival for HCC candidates. In addition, we will determine if AT can effectively down stage more advanced tumors and assess whether they can achieve post-LT survival outcomes equivalent to untreated, stage-matched controls as this may have implications for selection of HCC candidates for LT in the future. All of these studies will inform future liver allocation policy regarding the utility of liver transplantation for HCC compared with other indications and shed light on which, if any, pre-transplant treatments might be beneficial for patients with HCC waiting for liver transplantation. PUBLIC HEALTH RELEVANCE: More than 10000 Americans are waiting for liver transplantation and approximately 10% of the waiting candidates will die without ever being offered an organ. Organ allocation policy has granted significantly increased priority for candidates with HCC based on very few, poorly controlled, poorly powered, short-term studies. The goal of this application is to inform future HCC policy and practice by providing in depth characterization of long term survival and survival benefit outcomes for patients receiving liver transplantation for HCC indications using a unique, very large, comprehensive cohort.